Metastasis presents a major threat to the lives of breast cancer patients. Although the primary breast tumors can be surgically removed, the mortality rate of cancer remains high, mainly due to metastatic relapses. Breast cancer metastasis to the brain is increasingly becoming a significant clinical problem and its incidence is rising. This is largely attributable to the fact that current therapies, which are effective in controlling extracranial metastasis that prolong patient survival, are ineffective in controlling metastatic disease of the brain. My long- term goal is to elucidate the underlying mechanisms that mediate brain metastasis and therapeutic resistance of breast cancer at this metastatic site. Upon arrival in the distal organs, adaptation and survival of the tumor cells in the new microenvironment is a stringent rate-limiting step in establishing metastasis. My recent study identified mechanisms that support metastatic process in the lung by acting through direct physical interaction between tumor cells and lung leukocytes. As one of the main objectives of this project, I will assess whether parallel mechanisms between tumor cells and astrocytes, which are the most abundant non-neuronal cells in the brain, enhance brain metastasis and chemoresistance. The proposed aims will take a multidisciplinary approach, spanning molecular and biochemical analyses combined with sophisticated in vivo imaging and live animal studies, with the ultimate goal of rapidly translating the gained knowledge into new clinical practice. Another main objective of this project is to initiate and maintain a successful independent research program conducting high quality multidisciplinary research. To ensure successful completion of the objectives, I have identified two major areas I will fortify with continuous training: 1) scientific training through didactic courses on computational biology and clinical trials, obtaining guidance from my consultants/collaborators, and attending national meetings and 2) career developmental training through grant writing workshops, courses in responsible conduct of research, conflicts of interest, manuscript preparation and presentation workshops, and lab/budget management. With the protected time and stability afforded by the award, together with the collective training I will receive, I feel confident that I will be able to initite my own independent research program by successfully competing for RO1 funding. My short-term goals are to: 1. Secure an independent faculty position and expand my network of colleagues. 2. Identify molecular mechanisms mediating brain metastasis by completing the proposed aims. 3. Continue to advance my scientific development through consultants/collaborators and didactic courses. My long-term goals are to: 1. Further develop ongoing projects, devise and perform preclinical studies based on new results obtained. 2. Attain RO1 funding, expand research into other metastasis models, and continue my career development. 3. Translate our findings into new therapies, train future mentees, and maintain successful research program.